RESUMO
OBJECTIVE: To examine the Multiple Sclerosis Impairment Scale (MSIS) in secondary progressive MS (SPMS) in relation to the Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI) outcomes, and mobility. METHODS: In this observational single-center study, 68 secondary progressive multiple sclerosis (SPMS) patients were examined by MSIS, EDSS, functional mobility tests of upper/lower extremities, and multimodal MRI. Participants had EDSS ≥3.5, a decline in daily activities over the last year unrelated to relapses, and/or 6-month confirmed disability progression. RESULTS: Mean disease duration was 23.1 ± 8.3 years and mean age 54.4 ± 8.1 years. MSIS, EDSS, and their corresponding motor, cerebellar, and sensory subscores correlated (p < .0001). Motor subscores of MSIS correlated stronger with Timed-25-Foot-Walk (T25FW) than pyramidal functional system score (FSS) (p = .03), but EDSS had a stronger correlation to T25FW than the total MSIS score (p = .01). MSIS cerebellar subscore correlated stronger with 9-Hole Peg Test (9-HPT) than cerebellar FSS (p = .04). The sensory MSIS subscore also showed correlation with 9-HPT in contrast to sensory FSS (p = .006). MSIS subscores had stronger correlations with MRI volumetry measures than FSS scores (lesion volume and putamen, thalamus, corpus callosum volumetry, p = .0001-0.0017). CONCLUSION: In patients with SPMS, MSIS correlated with functional motor tests. MSIS showed stronger correlations with atrophy of central nervous system areas, and may be more sensitive to scale cerebellar and sensory function than EDSS.
Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Encéfalo/diagnóstico por imagem , Avaliação da Deficiência , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , CaminhadaRESUMO
BACKGROUND: Disease-modifying therapies (DMT) are increasingly used for children with multiple sclerosis (MS) even though most double-blinded randomized controlled trials evaluating efficacy, safety and dosing strategy of a specific drug have included adults. OBJECTIVE: To investigate predictors of treatment outcomes in patients with paediatric onset MS treated with DMTs. METHODS: Prospective cohort study from the nationwide Danish Multiple Sclerosis Registry including all patients with a MS diagnosis who initiated treatment with an approved DMT before the age of 18 (N = 137) and followed until their 25th birthday. Selected baseline predictors were tested in univariate and multivariate regression models. RESULTS: Multivariate analyses showed that being female and having disease duration for 2 or more years prior to DMT initiation predicted a higher relapse rate. In addition, disease duration and baseline expanded disability status scale (EDSS) predicted both confirmed disability worsening and improvement. We found no difference in treatment outcome between children with MS onset before and after the age of 13 years. CONCLUSIONS: The efficacy of DMT in paediatric onset MS patients is comparable to that seen in adult onset MS patients. Earlier treatment start is associated with a beneficial prognosis in the paediatric cohort.
Assuntos
Progressão da Doença , Intervenção Médica Precoce , Fatores Imunológicos/administração & dosagem , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros , Adolescente , Adulto , Idade de Início , Dinamarca , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Recidiva , Fatores Sexuais , Adulto JovemRESUMO
OBJECTIVES: In a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity. METHODS: We examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF. RESULTS: NFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001). CONCLUSIONS: This study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.
Assuntos
Fumarato de Dimetilo/efeitos adversos , Fumarato de Dimetilo/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Filamentos Intermediários , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
The aim of this study was to evaluate whether the six-spot-step test (SSST) is more suitable for monitoring walking ability in patients with chronic inflammatory polyneuropathy than the timed 25-foot-walking test (T25FW). In the SSST, participants have to walk as quickly as possible across a field measuring 1 × 5 m, while kicking blocks out of five circles on the floor. Sixty-two patients and 61 controls performed the SSST and T25FW. Patients also performed the overall disability sumscore, INCAT sensory sumscore, Medical Research Council sumscore, and 9-hole-peg-test. Twenty-one patients treated with intravenous immunoglobulin (IVIG) every 4-6 weeks were tested prior to and 2-3 weeks after treatment and judged change in their own clinical condition using the patient global impression of change (PGIC) scale. In patients, SSST ranged from 5.7 to 26.8 s and T25FW ranged from 3.6 to 12.9 s. Intra-class correlation between repeated tests was 0.97 for SSST and 0.95 for T25FW. Correlation with the additional tests was stronger for SSST than T25FW. In IVIG-treated patients, the mean change in walking time was -2.3 s for SSST and -0.6 s for T25FW. The SSST showed larger responsiveness in terms of effect size, standardized response means, and relative efficiency. Both ambulation tests correlated moderately to PGIC. The SSST may be superior to the T25FW in terms of dynamic range, floor effect, and responsiveness which makes the SSST a possible alternative for monitoring walking ability in patients with chronic inflammatory polyneuropathy.
Assuntos
Teste de Esforço , Transtornos dos Movimentos/etiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Caminhada/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Avaliação da Deficiência , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de SaúdeRESUMO
BACKGROUND: The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome and brain lesions on MRI. OBJECTIVE: To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe. METHODS: Patients with a clinically isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were randomized to receive glatiramer acetate 20 mg/d (early-treatment, n=198) or placebo (delayed-treatment, n=211) for 36 months or until conversion to CDMS, followed by open-label glatiramer acetate treatment for two years. RESULTS: Early glatiramer acetate treatment reduced CDMS conversion risk by 41% (hazard ratio 0.59, 95% confidence interval 0.44-0.80; p=0.0005) versus delayed-treatment, and was associated with a 972-day delay (185%) in conversion to CDMS, less brain atrophy (-28%, p=0.0209), fewer new T2 lesions/year (-42%, <0.0001) and lower T2 lesion volume (-22%, p=0.0005) versus delayed treatment. Adverse events were consistent with the established safety profile of glatiramer acetate. CONCLUSIONS: Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits.
Assuntos
Doenças Desmielinizantes/tratamento farmacológico , Imunossupressores/administração & dosagem , Peptídeos/administração & dosagem , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Doenças Desmielinizantes/patologia , Progressão da Doença , Método Duplo-Cego , Feminino , Acetato de Glatiramer , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/prevenção & controleRESUMO
Reduced depression of transmitter release from Ia afferents following previous activation (post-activation depression) has been suggested to be involved in the pathophysiology of spasticity. However, the effect of this mechanism on the myotatic reflex and its possible contribution to increased reflex excitability in spastic participants has not been tested. To investigate these effects, we examined post-activation depression in Soleus H-reflex responses and in mechanically evoked Soleus stretch reflex responses. Stretch reflex responses were evoked with consecutive dorsiflexion perturbations delivered at different intervals. The magnitude of the stretch reflex and ankle torque response was assessed as a function of the time between perturbations. Soleus stretch reflexes were evoked with constant velocity (175 degrees /s) and amplitude (6 degrees) plantar flexion perturbations. Soleus H-reflexes were evoked by electrical stimulation of the tibial nerve in the popliteal fossa. The stretch reflex and H-reflex responses of 30 spastic participants (with multiple sclerosis or spinal cord injury) were compared with those of 15 healthy participants. In the healthy participants, the magnitude of the soleus stretch reflex and H-reflex decreased as the interval between the stimulus/perturbation was decreased. Similarly, the stretch-evoked torque decreased. In the spastic participants, the post-activation depression of both reflexes and the stretch-evoked torque was significantly smaller than in healthy participants. These findings demonstrate that post-activation depression is an important factor in the evaluation of stretch reflex excitability and muscle stiffness in spasticity, and they strengthen the hypothesis that reduced post-activation depression plays a role in the pathophysiology of spasticity.
Assuntos
Depressão Sináptica de Longo Prazo/fisiologia , Espasticidade Muscular/fisiopatologia , Músculo Esquelético/fisiologia , Reflexo de Estiramento/fisiologia , Adulto , Idoso , Feminino , Reflexo H/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
BACKGROUND: More than half of all patients with multiple sclerosis (MS) acquire cognitive impairment as part of their disease progression. Because cognitive dysfunction adds substantially to disability and coping strategies, a cost-effective screening tool is needed for cognitive impairment. The Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) has previously shown good validity in American, Argentinean, and Dutch MS cohorts. We sought to test reliability and validity of a Danish translation of the MSNQ compared with formal neuropsychological testing, and measures of depression and disability, and to compare self-reported cognition with Symbol Digit Modalities Test (SDMT) results. METHODS: Of 126 patients with MS and their informants tested with the MSNQ, 77 also underwent formal neuropsychological testing. All patients were tested with the SDMT and assessed clinically using the Expanded Disability Status Scale and MS Impairment Scale. RESULTS: The test-retest reliability of the MSNQ-P was significant (R2 = 0.79, P < .0001). R2 of informants (MSNQ-I) and patients (MSNQ-P) was much lower (R2 = 0.22, P < .0001). Compared with formal neuropsychological testing, the MSNQ-P and MSNQ-I performed poorly, with no correlation to individual neuropsychological tests, combined neuropsychological tests, or disability scores (Expanded Disability Status Scale and MS Impairment Scale). Depression/anxiety (Beck Depression Inventory) showed a weak linear relationship (R2 = 0.25, P < .0001), suggesting that the MSNQ-P measures these items more than the cognitive abilities of the patients. CONCLUSIONS: This study does not support use of the MSNQ as a sensitive or valid screening tool for cognitive impairment in Danish patients with MS.
RESUMO
Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Seleção de Pacientes , Vigilância da População , Anticorpos Monoclonais Humanizados , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Imageamento por Ressonância Magnética , Natalizumab , Vigilância da População/métodos , Guias de Prática Clínica como AssuntoRESUMO
Cognitive impairment occurs in early multiple sclerosis (MS), may decline over time, and has major impact on social functioning. The objectives of this study were to examine cognitive functioning in newly diagnosed MS, and to follow up over a period of 5 years. The results of the first three yearly re-examinations are reported. Eighty newly diagnosed (<1 year) MS patients participated (male/female: 19:61, mean age: 35 years, mean EDSS 2.7, course: 75 relapsing-remitting, 3 primary progressive, 2 secondary progressive). Seventy-five healthy persons served as controls. The neuropsychological (NP) test battery comprised 30 test measures and was grouped into seven cognitive domains. A residual score of -1.5 SD as cut-off point was used to diagnose cognitive impairment. At the first examination, 44-48% had cognitive impairment. None of the patients were clinically depressed, 51% had no signs of depression on Beck Depression Inventory (BDI), and none had severe signs. Sixty-four patients completed four examinations, and a significant linear improvement over time was seen in three cognitive domains, no change in two domains, and deterioration in one domain. At the time of the fourth examination, 4.3 years since diagnosis, 33-34% of the patients had cognitive impairment. Thirty percent of the patients were on disablement pension, 34% received social services in relation to work and 13% had home care. Methodological problems are discussed, especially the practice effect and the importance of identifying sensitive and stable test measures.
Assuntos
Transtornos Cognitivos/fisiopatologia , Esclerose Múltipla/fisiopatologia , Adulto , Transtornos Cognitivos/classificação , Depressão/fisiopatologia , Escolaridade , Emprego/estatística & dados numéricos , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Análise Multivariada , Testes Neuropsicológicos/estatística & dados numéricos , Medição da Dor/métodos , Escalas de Graduação Psiquiátrica , Testes Psicológicos/estatística & dados numéricos , Reprodutibilidade dos Testes , Serviço Social/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
Cognitive dysfunction in multiple sclerosis (MS) is present in approximately 50% of the patients. Only moderate correlations have been found between cognitive dysfunction and T(2) lesion load, black holes or atrophy. Cognitive dysfunction in MS is probably related to the overall disease burden of the brain including abnormalities in normal appearing white matter (NAWM) and cortical grey matter, which is undetected with conventional magnetic resonance imaging (MRI). Hence, imaging techniques that embrace such abnormalities are needed to achieve better correlation with cognitive dysfunction. MR spectroscopy (MRS) performed with multi-slice echo planar spectroscopic imaging (EPSI) and PET measurements of brain metabolism as the cortical cerebral metabolic rate of glucose are imaging methods that are able to provide information on axonal loss or dysfunction in both MS lesions and in NAWM and cortical grey matter. Measurements of global NAA using multi-slice EPSI is a new promising method for measurement of the global neuron capacity and can be repeated with only little discomfort and without any risk for the patient.
Assuntos
Transtornos Cognitivos , Imageamento por Ressonância Magnética , Esclerose Múltipla/fisiopatologia , Tomografia por Emissão de Pósitrons , Mapeamento Encefálico , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Humanos , Espectroscopia de Ressonância Magnética , Esclerose Múltipla/patologia , Testes NeuropsicológicosRESUMO
BACKGROUND: Interferon beta is the first-line treatment for relapsing-remitting multiple sclerosis, but the drug can induce neutralising antibodies against itself, which might reduce effectiveness. We aimed to assess the clinical effect of neutralising antibodies. METHODS: We measured neutralising antibodies every 12 months for up to 60 months in 541 patients with multiple sclerosis, randomly selected from all patients who started treatment with interferon beta between 1996 and 1999. Patients left the study if they changed or discontinued therapy. Antibodies were measured blindly, using antiviral neutralisation bioassays with high, medium, and low sensitivity, and with different neutralising capacities as cutoff value for definition of a neutralising-antibody-positive result. FINDINGS: Patients developed neutralising antibodies independent of age, sex, disease duration, and progression index at start of treatment. Relapse rates were significantly higher during antibody-positive periods (0.64-0.70) than they were during antibody-negative periods (0.43-0.46; p<0.03). When comparing the number of relapses in the neutralising-antibody-positive and neutralising-antibody-negative periods we found odds ratios in the range 1.51 to 1.58 (p<0.03). Time to first relapse was significantly increased by 244 days in patients who were antibody-negative at 12 months (log rank test 6.83, p=0.009). During this short-term study, presence of neutralising antibodies did not affect disease progression measured with the expanded disability status scale. INTERPRETATION: Our findings suggest that the presence of neutralising antibodies against interferon beta reduces the clinical effect of the drug. In patients who are not doing well on interferon beta, the presence of such antibodies should prompt consideration about change of treatment.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Anticorpos/imunologia , Interferon beta/imunologia , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização/estatística & dados numéricos , Estudos Prospectivos , Prevenção Secundária , Resultado do TratamentoRESUMO
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease characterized by antibodies against aquaporin-4 in up to 80% of the cases and even less in the NMO spectrum disorders, which may be difficult to distinguish from early multiple sclerosis. While immunosuppressive therapy should be introduced in definite NMO, treatment strategies of NMO spectrum disorders are less clearly defined. Here, we review the current guidelines for treatment of NMO and NMO spectrum disorders in the light of two cases, and suggest a practical approach to the management of these disorders.
Assuntos
Neuromielite Óptica , Adulto , Algoritmos , Aquaporina 4/imunologia , Azatioprina/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Neuromielite Óptica/terapia , Plasmaferese , Guias de Prática Clínica como Assunto , Esteroides/uso terapêuticoRESUMO
This systematic review summarizes the existing evidence on the effect of 4-aminopyridine (4-AP) as a symptomatic treatment of decreased walking capacity in patients with multiple sclerosis (MS) when administered as an immediate release compound and a slow release compound. It summarizes existing evidence on the basic mechanisms of 4-AP from experimental studies and evidence on the clinical use of the compound. A systematic literature search was conducted of the following databases: PubMed and EMBASE. Thirty-five studies were included in the review divided into 16 experimental studies, two clinical studies with paraclinical endpoints and 17 clinical studies with clinical endpoints. Animal studies show that 4-AP can improve impulse conduction through demyelinated lesions. In patients with MS this translates into improved walking speed and muscle strength of the lower extremities in a subset of patients at a level that is often of clinical relevance. Phase III trials demonstrate approximately 25% increase in walking speed in roughly 40% and improved muscle strength in the lower extremities. Furthermore, 4-AP might have an effect on other domains such as cognition, upper extremity function and bowel and bladder, but this warrants further investigation. Side effects are mainly mild to moderate, consisting primarily of paraesthesia, dizziness, nausea/vomiting, falls/balance disorders, insomnia, urinary tract infections and asthenia. Side effects are worse when administered intravenously and when administered as an immediate release compound. Serious adverse events are rarely seen in the marketed clinical dosages. In conclusion, 4-AP is easy and safe to use. Slow release 4-AP shows more robust clinical effects and a more beneficial side-effect profile than immediate release 4-AP.
RESUMO
A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3-12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval [CI] 0.88-1.00), 0.47 (95 % CI 0.43-0.52) during natalizumab therapy, 0.63 (95 % CI 0.51-0.76) 1-6 months after natalizumab and 0.55 (95 % CI 0.42-0.70) 7-12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Fatores Imunológicos/efeitos adversos , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Adolescente , Adulto , Dinamarca , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Natalizumab , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
3,4-diaminopyridine (DAP) and 4-aminopyridine (AP) block potassium channels and can improve action potentials in demyelinated nerve fibres. We identified ten randomised placebo-controlled trials investigating AP/DAP as symptomatic treatment in multiple sclerosis. There is evidence that AP and DAP improve muscle strength in the lower extremities and that AP increases walking speed, and it might improve Expanded Disability Status Scale scores, spasticity and fatigue. There is a lack of evidence-based guidelines of treatment and studies investigating the effect on participation/activity and quality of life.
Assuntos
4-Aminopiridina/análogos & derivados , 4-Aminopiridina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , 4-Aminopiridina/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Amifampridina , Medicina Baseada em Evidências , Humanos , Extremidade Inferior/fisiopatologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/fisiopatologia , Força Muscular/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/efeitos adversos , Caminhada/fisiologiaRESUMO
Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Monitoramento de Medicamentos/normas , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Seleção de Pacientes , Guias de Prática Clínica como Assunto/normas , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Monitoramento de Medicamentos/métodos , Humanos , Integrina alfa4beta1/antagonistas & inibidores , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Natalizumab , Resultado do TratamentoRESUMO
BACKGROUND: Interferon beta is commonly used to treat patients with relapsing-remitting multiple sclerosis; however, the treatment is only partially effective in reducing relapses and progression of disability. Corticosteroids are used to treat relapses in patients with multiple sclerosis. We therefore aimed to investigate the combination of cyclic methylprednisolone and interferon beta for the treatment of relapsing-remitting multiple sclerosis. METHODS: In 2001, we designed a multicentre, double-blind, randomised, parallel-group trial, termed the methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN) study. Patients were recruited between October, 2002, and March, 2005 from 50 neurology departments in eight countries. We included treatment-naive patients with relapsing-remitting multiple sclerosis who had an expanded disability status scale (EDSS) score of 4 or less. Patients all started to receive interferon beta-1a and after 3 months were randomly assigned to add-on methylprednisolone or placebo 500 mg/day orally for 3 consecutive days per month for 3-4 years. Placebo tablets were identical to methylprednisolone tablets. Treating physicians, examining physicians, and patients were masked to treatment allocation. Patients were clinically assessed every 3 months and had brain MRI at baseline and 3 years later. The primary outcome was time to onset of disability progression, according to an increase in EDSS score sustained over 6 months. All patients who received at least one dose of study drug were included in all planned analyses. This trial is registered with ClinicalTrials.gov, NCT00168766. FINDINGS: 341 patients were randomly assigned to methylprednisolone (n=172) or placebo (n=169); 171 patients in the methylprednisolone group and 167 in the placebo group received at least one dose of study drug. 90 patients had sustained disability progression: 44 of 167 in the methylprednisolone group and 46 of 171 in the placebo group. The time to sustained progression did not differ between groups (hazard ratio 0.879, 95% CI 0.566-1.365; p=0.57). There were 1436 adverse events, 24 of which were serious, in the methylprednisolone group and 1070 events, 35 of which were serious, in the placebo group. INTERPRETATION: Monthly pulses of methylprednisolone in combination with interferon beta-1a do not seem to affect disability progression any more than interferon beta-1a treatment alone. More research is required to assess whether this treatment regimen might benefit particular subsets of patients. FUNDING: Biogen Idec.